Tissue mimicking elastography phantoms

ABSTRACT

Tissue mimicking materials for elastography phantoms have elastic, ultrasound, and magnetic resonance characteristics that are characteristic of human soft tissues and well suited for the calibration and performance assessment of elastography imaging systems. In one embodiment, the material is formed from a base material containing an oil dispersed within a gel matrix and at least one inclusion formed from a gel. In another embodiment, the material is formed from a gel-forming material suffused throughout an open-cell reticulated mesh matrix.

STATEMENT OF GOVERNMENT INTEREST

[0001] This invention was made with United States government supportawarded by the following agency: NIH Grant No. RR14365. The UnitedStates government has certain rights in this invention.

FIELD OF THE INVENTION

[0002] This invention pertains generally to materials for testing theperfomance of ultrasound and magnetic resonance elasticity imagingequipment.

BACKGROUND OF THE INVENTION

[0003] The early detection of cancer using medical imaging equipmentrequires the ability to detect small lesions or to delineate theboundaries of lesions that have properties close to those of thesurrounding normal tissue. The measure of the smallest object visiblewith a given contrast is called the contrast detail resolution of theimaging system. Contrast-detail resolution and other performance testsof a medical imaging system are performed with objects called phantoms.A phantom with a variability of size and contrast objects is requiredfor the evaluation of the contrast-detail resolution of the system. Suchphantoms are commercially available for use with X-ray computedtomography, ultrasound imaging systems, and nuclear magnetic resonanceimaging systems but are not generally available for the ultrasound andmagnetic resonance elasticity imaging systems used in elastography.Elastography is a relatively recent technology directed at the earlydetection of tumors. Over the last decade, elastography has beenrecognized as having great potential as a tool for breast and prostatecancer diagnosis. In addition it may also play an important role inareas such as monitoring tumor ablation therapy and intravascular plaqueclassification. Presently, there is a great need for temporally stableheterogeneous phantoms to enable vigorous development and testing ofelastographic hardware and software.

[0004] Elastography is the investigation of tissue elasticity usingultrasound methods. In ultrasound elastography (USE), an axial stress isapplied to a tissue and the resulting strain of the tissue is determinedfrom the change in the ultrasound echo signals before and after theapplication of the stress. With USE, a sample of tissue can becharacterized by mapping out the local elastic strain of the analyzedtissue. The resulting mapping is called an elastogram. Hard tumormaterial will show less strain than softer tissues and this contrastbetween the elastic properties is picked up on an elastography image.The technique has the advantage of adding new diagnostic information toconventional ultrasound imaging.

[0005] Magnetic Resonance Elastography (MRE) is a particularly sensitivetechnique that couples the power of nuclear magnetic resonance imagingwith the complementing information of elastography. There are twoprimary forms of MRE, harmonic MRE and quasistatic MRE. In harmonic MREtissues are exposed to a deforming force at a frequency of 50-1000 Hz,generating longitudinal and shear waves throughout the tissue. In thismethod, an oscillating magnetic field gradient is used to induce spinphase change in proportion to the amplitude of the tissue motion. Thetissue motion, or deformation, is measured by use of a phase contrastmagnetic resonance technique and displayed in the form of an image. Thequasistatic technique uses very low deformation frequencies between 0and 1 Hz. In this method, wave propagation can be assumed to benegligible, with the tissue in an approximate state of static stress.

[0006] In addition to mimicking the elastic properties of soft tissue,the ideal tissue mimicking material for use in USE should have the sameranges of speeds of sound, attenuation coefficients, and backscattercoefficients as soft tissue. These parameters should be controllable inthe manufacturing process of the phantom material, and their variationwithin the range of room temperatures should be small. Speeds of soundin human soft tissues vary over a fairly small range with an averagevalue of about 1540 m/s. The speed of sound in fat is thought to beabout 1470 m/s. The amplitude attenuation coefficients appear to varyover the range from 0.4 dB/cm to about 2 dB/cm at a frequency of 1 MHzin these tissues. The frequency dependencies of the attenuationcoefficient of some soft tissues have been studied and, typically, ithas been reported that the attenuation coefficient is approximatelyproportional to the ultrasonic frequency in the diagnostic frequencyrange of 1 to 10 MHz. An exception is breast fat, in which theattenuation coefficient is proportional to the frequency to the 1.7power. This is discussed in F. T. D'Astous and F. S. Foster, “FrequencyDependence of Attenuation and Backscatter in Breast Tissue,” Ultrasoundin Med. & Biol., Vol. 12, pp. 795-808 (1986).

[0007] For use in elastography, the tissue mimicking materials mustexhibit the same Young's modulus as that of the tissue being mimicked.The Young's modulus varies significantly from tissue to tissue. Krouskopet al., have reported in vitro values for the Young's moduli (E) fornormal and abnormal breast and prostate tissues using precompression andlow frequency superimposed sinusoidal loading. At 5% precompression inbreast and 4% in prostate cases, E ranged from 18±7 kPa for breast fatthrough 241±28 kPa for prostate cancer. The Young's modulus for normalbreast glandular tissue was found to be approximately 30 kPa and theYoung's modulus for invasive and infiltrating ductal carcinoma wasaround 100 kPa.

[0008] Phantoms for use in MRE should also possess nuclear magneticresonance properties reflective of those found in human soft tissues.Soft tissues exhibit T1's ranging from about 200 milliseconds (ms) toabout 1200 ms and T2's from about 40 ms to about 200 ms. Typical valuesfor the ratio T1/T2 lie between about 4 and about 10 for soft tissues.For a given soft tissue parenchyma, T1 in particular can exhibit asignificant dependence on frequency as well as temperature.

[0009] Each of the above-mentioned parameters should be controlled inorder to provide the desired range of values in the manufacturingprocess of the phantom, and should agree at all frequencies in theclinical ultrasound range of 1-10 MHz. In addition, the materials shouldpossess long-term stability over periods of months or years with respectto the elastic, ultrasound, and magnetic resonance properties, and withrespect to geometries, such as inclusion size and shape. Moreover, ifthe phantom includes inclusions of materials within the surroundingmatrix which have different elastic, ultrasound and magnetic resonanceproperties than the surrounding matrix, these inclusions must be stableover time in both size and shape and in physical and chemicalproperties.

[0010] Materials which have been proposed for use in elastographyphantoms to mimic soft tissues include homogeneous gels of gelatin andhomogeneous gels of agar. The gelatin phantoms typically include aparaldehyde or formaldehyde crosslinking agent. The Young's modulusvalues for such phantoms depend on the dry weight of agar or gelatin inthe gels, and in the case of gelatin, on the concentration of theformaldehyde or paraldehyde used to crosslink the materials. Suchphantoms have been in use as ultrasound phantoms for many years. Thesematerials suffer from several drawbacks. First, homogeneous agar gelsbond only weakly together, therefore an agar inclusion will not bestrongly bonded to its agar surroundings in a phantom. In addition agargels are brittle and fracture at modest strains. In contrast,homogeneous gelatin gels possess durable inclusions that bond well togelatin surroundings. However, it is very difficult to produce stableelastic contrast in these phantoms because the inclusions and thesurrounding materials are made from gelatin having varying dry weightconcentrations of gelatin and formaldehyde, and there is a strongtendency for the materials to approach a uniform concentration ofgelatin and formaldehyde over time through diffusion. In addition,gelatins cannot be made to possess adequately large T1/T2 ratios tosimulate soft tissues.

[0011] Another phantom that has been proposed for use in elastographyimaging systems is a heterogeneous phantom having a gelatin section andan agar component. Unfortunately, the Young's modulus for the agarcomponent in such phantoms was found to increase by a factor of 6 forstrains between about 2% and 7%. It has been found that the Young'smoduli of normal fat, breast and prostate parenchyma exhibit only asmall dependence on strain over similar strain ranges. Thus, for strainsof less than about 10%, it does not appear that agar by itself is asuitable material for mimicking normal breast or prostate tissue.

[0012] Polyvinyl alcohol gels have also been investigated regardingtheir suitability for magnetic resonance elastography phantoms. However,these materials do not possess long-term stability and are significantlystiffer than biological soft tissue.

[0013] Silicone rubber has also been tested for use with magneticresonance elastography. Unfortunately, the speed of propagation of soundin silicone rubber is too low for this material to be a realistic optionfor ultrasound elastography studies.

[0014] Other phantoms for use in elastography include phantoms made frommixtures of agar and gelatin. One such phantom is made from 8% gelatinand between 1 and 3% agar, based on the dry weight of the materials, inthe absence of a crosslinking agent. The Young's moduli of thesematerials are significantly temperature dependent at temperaturesbetween 5° C. and 40° C. and the materials do not possess long-termstability with respect to shape and physical properties.

[0015] A phantom of this type is described in U.S. Pat. No. 5,312,755 toMadsen et al. This patent discloses a tissue mimicking NMR phantom thatutilizes a base tissue mimicking material which is a gel solidified froma mixture of animal hide gelatin, agar, water and glycerol. The amountof glycerol can be used to control the T1. The preferred base materialincluded a mixture of agar, animal hide gelatin, distilled water(preferably deionized), glycerol, n-propyl alcohol, formaldehyde, andp-methylbenzoic acid. The contrast-detail resolution phantom couldinclude inclusions which have NMR properties which differ from the basetissue mimicking material. Differences in contrast between thesurrounding base material and the spherical inclusions could also beobtained by the use of a solid such as powdered nylon added to the basematerial and the inclusions that has little NMR response but displacessome of the gelatin solution, decreasing the apparent ¹H density to theNMR instrument.

[0016] Phantom materials composed of water based agar gels doped withMnCl₂ to control T1 for use in conventional magnetic resonance imagingsystems have been reported. R. Mathur-DeVre-, et. al., “The Use of Agaras a Basic Reference for Calibrating Relaxation Times and ImagingParameters,” Magn. Reson. Med., Vol. 2, 1985, p. 176. Agar gels dopedwith CuSO₄ have also been reported. M. D. Mitchell, et al., “Agarose asa Tissue-Equivalent Phantom Material for NMR Imaging,” Magn. Reson.Imag., Vol. 4, 1986, p. 263.

[0017] A phantom material consisting of mixtures of agar gel and animalhide gel in which CuSO₄ was used to lower T1 for use in conventionalmagnetic resonance imaging has also been reported. Unfortunately, along-term instability manifested itself in that a steady, very slow risein T1 was observed over a period of months. This instability precludesthe use of this material in magnetic resonance phantoms. The rise in T1was perhaps due to the slow formation of metal-organic complexes,removing the Cu⁺⁺ paramagnetic ions. See J. C. Blechinger et al., “NMRProperties for Tissue-Like Gel Mixtures for Use as Reference Standardsor in Phantoms,” Med. Phys., Vol. 12, 1985, p. 516 (Abstract). Morerecently, the problem of gradual increase in T1 in the agar, animal hidegel, Cu⁺⁺SO₄ ⁻ gel has been eliminated by addition of the chelatingagent EDTA (ethylenediaminetetraacetic acid). This stable material isexcellent for use in MRI phantoms. See J. R. Rice, et al.,“Anthropomorphic ¹H MRS Head Phantom,” Med. Phys., Vol. 25, 1998, pp.1145-1156.

[0018] Further ultrasound and MRI phantoms are illustrated in U.S. Pat.Nos. 6,238,343 and 6,318,146.

SUMMARY OF THE INVENTION

[0019] The present invention provides heterogeneous tissue mimickingphantoms for use in the testing and development of elastography imagingsystems. In accordance with the invention, a tissue mimicking materialis provided for imaging phantoms that can be used with ultrasoundelastography and magnetic resonance elastography. The tissue mimickingmaterial may be adjusted to appropriately mimic human tissue forparticular normal tissues including organs, skeletal muscle, and fat.Abnormal tissues such as cancer and fibroadenomas can also berepresented. The materials mimicking the various tissues may beincorporated in direct contact with one another in an imaging phantomand remain stable in their elastography imaging properties over time,allowing such phantoms to be used for long-term calibration andevaluation of the imaging instruments. Phantoms in accordance with theinvention have particular application in simulating normal and abnormalbreast and prostate tissue which is surrounded by and adjacent to muscleand fat tissue.

[0020] As used herein, the phrase “tissue mimicking material” refers toany material having elastic, ultrasound, and/or magnetic resonanceproperties that are sufficiently similar to the elastic, ultrasound,and/or magnetic resonance properties of real soft tissues to produceelastograms having an elastic contrast that allows the performance ofthe elastography imaging equipment to be qualitatively or quantitativelyevaluated. The primary elastic properties of interest are the Young'smodulus of the material and the elastic contrast between differentmaterials. In a preferred embodiment, a tissue mimicking phantom will bemade of materials having an elastic contrast that is within 20 percent,preferably within 10 percent, and more preferably within 5 percent ofthe real soft tissues being mimicked or modeled by the phantom.

[0021] The primary ultrasound properties of interest include the speedof sound in the materials and the attenuation and backscatteringcoefficients of the materials. In various preferred embodiments, thespeed of sound in the materials in the phantoms will be within 25percent, preferably 20 percent, and more preferably 10 percent of thespeed of sound in the real soft tissues being mimicked or modeled.

[0022] The primary magnetic resonance properties of interest are the T1and T2 values and the T1/T2 ratios of the materials. In variouspreferred embodiments the T1 and T2 values of the phantom materials willbe within 25 percent, preferably within 20 percent, and more preferablywithin 10 percent of the T1 and T2 values of the real soft tissues beingmimicked or modeled.

[0023] In accordance with one aspect of the present invention, a tissuemimicking phantom includes an elastography phantom container with a basetissue mimicking material therein made from an oil dispersed throughouta gel matrix formed from a gel-forming material and at least oneinclusion which is at least partially embedded in the base material. Theinclusion is also formed from a gel-forming material, preferably thesame gel-forming material found in the base material. The inclusion gelmay also have an oil dispersed in it, usually at a differentconcentration than in the base material. In this embodiment the elasticproperties, and the Young's modulus in particular, of the tissuemimicking base material and the inclusion material are different, givingrise to an elastic contrast in the phantom, where elastic contrast issimply the ratio of the Young's modulus of the inclusion to the Young'smodulus of the base, or background material. The gel-forming material inthe base material and in the inclusion may comprise a gelatin or amixture of agar and gelatin. The gel-forming material in the inclusionmay comprise a homogeneous congealed gelatin or agar/gelatin mixture. Invarious embodiments, microscopic solid particles are dispersedthroughout the base material and/or the inclusion to create softtissue-like ultrasound attenuation coefficients. Powdered graphite,powdered nylon, concentrated bovine milk, and glass or plastic beadshaving a diameter of less than 40 micrometers (μm), and preferably lessthan 25 μm can be used to vary the attenuation coefficients of thephantom materials. In addition, larger solid particles (greater then 30μm diameter) may be dispersed in either the base or the inclusionmaterial to create soft tissue-like ultrasound backscattering. Glass orplastic beads and powdered nylon may be used to enhanced ultrasoundbackscatter.

[0024] Preferred inclusions are spherical or cylindrical in form and maybe arranged so that several inclusions which span a range of diametersdown to the smallest diameter which may generally be imaged byultrasound or magnetic resonance elastography imaging apparatus areprovided (e.g., from several centimeters to a minimum size in the rangeof 1 millimeter).

[0025] Enhanced dimensional and elastic stability can be achieved for aphantom when the chemical composition of the gel-forming material in thegel matrix of the base material and the gel-forming material in theinclusion are the same material. This prevents the diffusion of solventsand solutes between the base material and the inclusion, resulting in aheterogeneous phantom having ultrasound, elastic, magnetic resonance,and shape characteristics that do not change over long times.

[0026] Where the phantom is to be used in MRE studies, a mixture of acopper salt and a chelating agent for binding the copper ions of thesalt may be added to the gel forming material in the base and/or theinclusion to produce a more tissue-like T1 value. A preferred coppersalt is CuCl₂ and a preferred chelating agent isethylenediaminetetraacetic acid (EDTA).

[0027] The tissue mimicking base materials and inclusions of thisinvention can be made to have Young's moduli, attenuation coefficients,backscattering coefficients, and speeds of sound which reflect theranges found in normal and abnormal soft tissues. Some of the materialsof the present invention are elastically linear for strains of up to10%, that is, the Young's moduli for the materials are constant forstrains of up to 10%. Heterogeneous phantoms made from these materialsproduce elastic contrast values between approximately 1 and 4,preferably between 1 and 3, which reflects the range of elastic contrastfor actual tumors in soft tissue. In addition, the materials can beproduced with hydrogen T1/T2 ratios, as well as T1 and T2 values, whichspan the ranges found in normal and abnormal soft tissues. The frequencydependence of US attenuation coefficients found for these materials alsosimulates that found in nonfat type soft tissues, and the materialsexhibit long term stability in their elastic, ultrasound, and magneticresonance properties. These materials do not shrink or extrude solutionat their boundaries, and therefore are satisfactory for the constructionof complex phantoms.

[0028] Another aspect of the invention provides a mesh-based tissuemimicking material comprising an open cell reticulated mesh materialhaving a gel-forming material suffused throughout its interstices. Thesematerials have a higher Young's modulus than materials made from ahomogenous congealed gelatin. Examples of suitable mesh materialsinclude polymer meshes, such as polyurethane and polyether meshes,having between about 10 and about 30 cells per inch. The gel-formingmaterial may comprise a gelatin or a mixture of agar and gelatin. In apreferred embodiment the gel-forming material is made of pure agar. Agaris elastically nonlinear over strains of up to at least 10%. Therefore,these materials can be used as inclusions in a heterogeneous phantom tosimulate tumors which exhibit nonlinear elasticity. The gel-formingmaterial suffused within the mesh may take the form of a double layer ofgel-forming material comprising an inner volume of agar and an outershell of a gelatin-containing gel-forming material that surrounds theinner volume. The inner volume and outer shell may both be substantiallyspherical in shape, or the inner volume may be substantially sphericalwith an outer shell having spicules extending therefrom to simulatespiculated tumors.

[0029] The invention further provides a tissue mimicking phantom havinga phantom container defining an interior space with a base materialtherein comprising a gel-forming material at least partially surroundingat least one mesh-based inclusion of the type described above. Thegel-forming material of the base may comprise gelatin or a mixture ofagar and gelatin. In addition, the gel-forming material of the baseand/or the inclusion may contain a crosslinking agent. In a preferredembodiment, both the base and the inclusion contain gelatin and acrosslinking agent such that crosslinks may be formed between thegelatin of the base and the gelatin of the inclusion, preventingslipping at the base-inclusion boundary.

[0030] Yet another aspect of the invention provides a tissue mimickingmaterial composed of millimeter (mm) sized agar spheres suspended in acrosslinked gelatin matrix. Agar is itself elastically nonlinear overstrain ranges typically encountered in elastography studies. Therefore,a tissue mimicking material containing pure agar spheres surrounded bygelatin provides a good representation of elastically nonlinear tissuesand tumors. The agar spheres are preferably closely packed within thegelatin, exhibiting a volume fraction of at least 30 percent, preferablyat least 50 percent, more preferably at least 70 percent, and mostpreferably at least 75 percent of the material. The agar spheres aremade from a mixture of agar powder and water. In a preferred embodimentthe agar will be present in an amount of less than 2 weight percent ofthe mixture, based on the dry weight of the agar.

[0031] Further objects, features, and advantages of the invention willbe apparent from the following detailed description when taken inconjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In the drawings:

[0033]FIG. 1 shows an ultrasound elastogram (left) and a magneticresonance elastogram (right) for a phantom composed of a 50%oil-in-gelatin base material and a gelatin inclusion. Also shown are thelateral (left) and axial (right) strain profiles for the elastogramstaken on two different days (Jan. 4, 2002 (solid), and Jan. 15, 2002(dashed)). The vertical axis in the strain profiles represents strainand the horizontal axis represents centimeters.

[0034]FIG. 2 shows ultrasound B-scan images (left) and elastograms(right) for a phantom composed of a 32% oil-in-gelatin base material anda graphite-in-gelatin inclusion. Images and elastograms were made 4(top), 5 (center) and 6 (bottom) months after production of the phantomand demonstrate long-term geometrical stability. The correspondinglateral (left) and axial (right) elastic strain profiles for theelastograms demonstrating long-term stability of elastic properties areshown in the lower panels. The elastic strain profiles were taken onNov. 16, 2001 (solid), and Dec. 15, 2001 (dashed). The vertical axis inthe strain profiles represents strain and the horizontal axis representscentimeters.

[0035]FIG. 3 shows ultrasound elastograms for a phantom composed of a50% oil-in-agar/gelatin base material and an agar/gelatin inclusion,taken on two different days (Jan. 4, 2002, and Jan. 15, 2002). Alsoshown are the lateral (left) and axial (right) strain profiles taken onJan. 4, 2002 (solid), and Jan. 15, 2002 (dashed). The vertical axis inthe strain profiles represents strain and the horizontal axis representscentimeters.

[0036]FIG. 4 is a side view of an exemplary elastography phantom inaccordance with the invention.

[0037]FIG. 5 is a top view of the elastography phantom of FIG. 4.

[0038]FIG. 6 is a top view of the phantom described in Example 5. Thespheres containing 30% oil provide the lowest elastic contrast and thespheres containing 0% oil provide the highest elastic contrast.

[0039]FIG. 7. is a side view of the phantom described in Example 5.

DETAILED DESCRIPTION OF THE INVENTION

[0040] The present invention provides tissue mimicking materials andheterogeneous phantoms for use in the testing and development ofelastography imaging systems. The phantoms of the present inventionprovide long term stability in terms of both shape and elastic andmagnetic resonance properties. This is very important because remakingphantoms as they deteriorate is costly in terms of time and money,particularly because the characterizing parameters (Young's modulus,ultrasound propagation speed, ultrasound attenuation coefficients,elastic contrast, and the two magnetic resonance relaxation times) needto be redetermined for each new phantom.

[0041] The materials of the present invention can be designed to closelymimic the elasticity characteristics of soft tissue. In particular, thephantom materials possess Young's moduli of between about 10 and about300 kPa, preferably between about 10 and about 270 kPa, and morepreferably between about 30 and about 100 kPa, at 5% precompression. Theelastic contrast for the various materials in the phantoms may typicallybe between about 1 and about 4 and preferably between about 1 and about3. In addition, the speed of sound propagation in the materials rangesfrom 1300 m/s to 1650 m/s at room temperature (i.e., about 22° C.) whichmimics the speed of sound in various fat, non-fat, and tumor tissues.The materials also possess attenuation coefficients of between about 0.1dB/cm/MHz and about 2.0 dB/cm/MHz, which includes the attenuationcoefficients from fat (0.4 dB/cm/MHz) through muscle (1.5 dB/cm/MHz). Inthe case of materials for use in magnetic resonance elastography, thehydrogen density and relaxation times (T1and T2) of the materials can bemade to reflect those of several types of tissues. For examples, Tl'sranging from about 200 milliseconds (ms) to 1200 ms and T2's from about40 ms to 200 ms can be produced in the materials, with values for theratio T1/T2 between 4 and 10.

[0042] One aspect of the invention provides a tissue mimicking phantommaterial composed of a base material made from an oil dispersed in agel-forming material and at least one inclusion suspended in and incontact with the base material. The inclusion is itself composed of agel-forming material, preferably the same gel-forming material used toform the base material. The inclusion material could also contain oildispersed in it at a different concentration than in the backgroundmaterial. In a preferred embodiment, the gel-forming material is a gelsolidified from gelatin, such as animal hide gelatin, or a mixture ofgelatin and agar. The oil is preferably safflower oil, but may be oliveoil, castor oil, or kerosene. The hardness of the base and inclusionmaterials can be adjusted by changing the percent oil in the dispersion.The gel-forming materials of the invention are crosslinked by addingsuitable crosslinking agents, such as paraaldehyde or formaldehyde, tothe gel-forming material during the congealing process, described inmore detail below.

[0043] The tissue mimicking base and inclusion materials may containsolid scattering particles dispersed throughout the gel-forming materialto increase backscattering and attenuation to levels that are reflectiveof backscattering and attenuation levels in various types of normal andabnormal soft tissue. The use of such particles allows a wide range ofscattering and attenuation levels to be achieved. Suitable solidparticles for increasing attenuation include powdered graphite, powderednylon, and glass or plastic beads, having a mean diameter of less than20 μm. Concentrated bovine milk can also be added to increaseattenuation. The scattering particles should be large enough to inducescattering and spaced sufficiently close to each other that anultrasound scanner is incapable of resolving individual scatteringparticles. Powdered nylon and glass or plastic beads having a meandiameter of greater than 30 μm may be used to enhance backscattering.The addition of scattering particles is particularly useful forsimulating muscle tissue. If glass or plastic beads are used, theyshould be selected and treated to have a low effect on the relaxation(T1 and T2) properties of the tissue mimicking materials. For example,glass beads may be treated by soaking them in nitric acid to clean thesurfaces thereof to reduce the effect of any surface contamination onthe magnetic resonance properties.

[0044] In order to optimize the ultrasound and/or the magnetic resonancecharacteristics of the materials for use as tissue mimicking phantoms,organic hydroxy compounds may be added to the gel-forming materials inorder to increase the speed of sound to levels similar to those found insoft tissue and to lower T1 to a value in the range of T1 values foundin soft tissues. This is particularly advantageous for oil-in-gelatindispersions which tend to have a lower speed of sound than real softtissue. Organic hydroxy compounds that may be used to alter the speed ofsound in gel-based emulsions are well known in the art. Examples of suchcompounds include, but are not limited to, n-propanol, glycerol,ethanol, and ethylene glycol. Glycerol is particularly suitable because,in addition to increasing the speed of sound in the material, theglycerol content can be varied to control the value of T1 independentlyof T2, since the glycerol to water ratio has little effect on the T2value of the material. Glycerol is also insoluble in oil which isadvantageous because the phantoms are typically stored in vegetable oil.Thus, this tissue mimicking material can be produced in the propermixture of components to have T1/T2 ratios, as well as T1 and T2 values,which span the ranges found in normal and abnormal soft tissues. Thefrequency dependence of T1 and T2 in the tissue mimicking materialsimulates that found in nonfat type soft tissues, and the materialexhibits long term stability of the T1 and T2 values. An inorganic salt,such as NaCl, can also be added to increase the ultrasonic speed. Such amaterial also has the advantage that it is insoluble in the vegetableoil in which the phantoms may be stored.

[0045] For tissue mimicking materials that are designed for use with MREimagers it is desirable to add a Cu⁺⁺ copper salt and a chelating agentinto the gel-forming material in order to lower the T1 value to a softtissue-like value. The use of a copper salt and chelating agent to lowerT1 may be utilized as described in J. R. Rice, et al., “Anthropomorphic¹H MRS Head Phantom,” Medical Physics, Vol. 25, 1998, pp. 1145-1156. Anappropriate chelating agent is EDTA. EDTA binds to the Cu⁺⁺ and preventsimobilization of the Cu⁺⁺ through the formation of metal-organiccomplexes with the rigid agarose or other gel that may be used. Thus,the use of CuCl₂ and EDTA together, forming mobile paramagneticparticles, results in a stable T1.

[0046] In addition, the gel-forming materials in the tissue mimickingmaterials may include components which stabilize the material againstattack by micro-organisms, particularly bacterial attack. For example,n-propanol, formaldehyde, p-methylbenzoic acid, and thimerosal (thesodium salt of ethylmercurithiosalicyclic acid) can be utilized toprevent bacterial invasion, with the formaldehyde also functioning as acrosslinking agent for the gelatin molecules.

[0047] In one preferred embodiment of the invention the base materialcomprises a 50% (volume percent) safflower oil-in-calfskin gelatindispersion and the inclusion comprises a homogeneous congealed calfskingelatin. In both the base and the inclusion, the gelatin comprises amixture of calfskin gelatin, thimerosal, glass beads (22 μm diameter),and formalin (a formaldehyde solution) which serves to crosslink thegelatin. The bead concentration in the materials was approximately 4grams of 3000 E Potters beads (Potters Industries, Valley Forge, Pa.)per liter.

[0048] In another preferred embodiment of the invention the basematerial comprises a 32% (volume percent) safflower oil-in-calfskingelatin dispersion and the inclusion comprises a powderedgraphite-in-calfskin gelatin dispersion. In both the base and theinclusion, the gelatin comprises a mixture of calfskin gelatin,thimerosal, glass beads (22 μm diameter) and formalin. The beadconcentration in the materials was approximately 4 grams of 3000 EPotters beads (Potters Industries, Valley Forge, Pa.) per liter.

[0049] In yet another preferred embodiment of the invention, the basematerial comprises a 50% (volume percent) safflower oil-in-agarosegelatin dispersion and the inclusion comprises a homogeneous congealedagarose gelatin. In both the base and the inclusion the agarose gelatincomprises an aqueous mixture of agar, calfskin gelatin, thimerosal,glass beads (22 μm diameter), CuCl₂ and EDTA. The CuCl₂ and EDTA arepresent to lower the T1 value of the material.

[0050] The following is an exemplary general technique for producing atypical phantom tissue mimicking material having a gelatin inclusionembedded in an oil-in-gelatin base material according to the presentinvention. First, an aqueous molten gelatin for incorporation into aninclusion is formed by combining a dry gelatin powder with distilledwater. The mixture is heated at a temperature and for a time sufficientto clarify the solution. Optionally, a small amount of preservative, anorganic hydroxy compound, a copper salt and a chelating agent, andmicroscopic attenuating particles and/or scattering particles may beadded to the mixture in order to produce more tissue-like elastic,ultrasound, and magnetic resonance properties. The gelatin and anyadditives are mixed well, being careful not to introduce any air intothe mixture. The mixture is allowed to cool and an amount ofcrosslinking agent sufficient to crosslink the gelatin is added to themixture, typically between about 5 and about 15 ml per liter of thegelatin mixture of formalin will be sufficient for this purpose.

[0051] The amount of organic hydroxy compound added to the mixtureshould be sufficient to raise the speed of sound in the material to atissue-like value. The actual amount required will vary depending on thenature of the hydroxy compound and the type of tissue to be simulated,however, for a typical oil-in-gelatin dispersion the mixture willcontain between about 60 ml and about 100 ml of n-propanol per liter ofmaterial. Similarly, the amount of attenuating and/or scatteringparticles added should be sufficient to increase the ultrasoundattenuation and scattering to a range that is representative of softtissue. Again, the amount required to achieve this will vary dependingupon the nature of the particles and the characteristics of the type oftissue to be simulated, however, for a typical gelatin inclusion,between about 20 and about 100 grams of attenuating particles andbetween about 1 and about 8 grams of scattering particles should beadded per liter of mixture.

[0052] If a copper salt and a chelating agent are included in thegelatin mixture the amount added should be based on the desired T1 valueof the tissue to be simulated. Typically, the copper salt will beCuCl₂.2H₂O and will be present in an amount between about 0.2 grams andabout 1.8 grams per liter of gelatin solution. The chelating agent willtypically be EDTA-tetrasodium salt hydrate (MW=380.2) in an amountbetween about 0.43 grams and about 3.9 grams per liter of gelatinsolution.

[0053] Next the mixture is poured into a mold. The mold is then sealed,placed under positive pressure, and rotated about a horizontal axis at arate and for a time sufficient to congeal the gel-forming materialwithout sedimentation of any attenuating or scattering particles. Themolds are typically two part acrylic molds held together with holes andpegs to produce an exact alignment. The molds may be coated with a thinlayer of petrolatum to prevent sticking and facilitate removal of thecongealed inclusion. Such molds can be used to produce spherical orirregularly shaped three dimensional simulated tumors.

[0054] A typical tissue mimicking oil-in-gelatin base material, inaccordance with the present invention, may be made according to thefollowing steps. First, an aqueous molten gelatin is formedsubstantially as described above for the inclusion, with the exceptionthat an oil is now added to the gelatin mixture, along with anypreservatives, organic hydroxy compounds, copper salts, chelatingagents, or scattering and attenuating particles. The amount of oil addedshould be sufficient to provide a dispersion having elasticity,ultrasound, and magnetic resonance characteristics that reflect thosefound in soft tissues. A higher percent of oil in the dispersionproduces a less stiff material having a lower Young's modulus. Theamount of oil required will depend on the Young's modulus desired.However, for a typical oil-in-gelatin emulsion the volume percent of theoil in the dispersion is preferably between about 20 and about 60 volumepercent. A surfactant is added to facilitate dispersion of the oil intosufficiently small droplets that they are not visible to the naked eye(typically less than about 30 μm in diameter). Typically, 7.5 cc ofliquid Ultra Ivory®, produced by the Proctor and Gamble Company, issufficient for adequate emulsification. The gelatin, oil, and anyattenuating or scattering particles are mixed well, being careful not tointroduce any air into the mixture, to produce an oil-in-gelatindispersion. The mixture is allowed to cool and an amount of crosslinkingagent sufficient to crosslink the gelatin is added to the mixture.

[0055] Once the congealed inclusions and the molten oil-in-gelatindispersion have been formed, the inclusions are embedded in the basematerial such that the inclusions and the base material are in directcontact and are bonded to one another. This can be accomplished byremoving the congealed inclusions from their molds and suspending themwith stainless steel wire (0.1 or 0.3 mm) in larger, usually one-piece,molds and pouring the molten oil-in-gelatin dispersion into the largermold such that it surrounds or partially surrounds the inclusion. Thewires may be covered with a thin layer of petrolatum to facilitatewithdrawal once the base material is congealed around the inclusions.The larger mold is then sealed, placed under positive gauge pressure,and rotated at a rate and for a time sufficient to congeal thegel-forming material without sedimentation of the oil or anyattenuating/scattering particles. After the base material has beencongealed, the mold is placed in an oven at about 50° C. for a timesufficient to hasten the completion of crosslinking of the gelatin bythe crosslinking agent (typically at least 3 days). Without baking,crosslinking is typically completed within one month.

[0056] Although the baking process likely aids in crosslinkingcompletion, the most dramatic effect is the lowering of the Young'smodulus. In fact, it is the latter effect that is likely the mostimportant and useful in that the ranges of Young's moduli available isbroadened and lowered, to produce materials that are suitable for use intesting elastography images. This effect is illustrated in Example 6below.

[0057] Alternatively, phantoms having cylindrical inclusions can beformed by first pouring the molten oil-in-gelatin material describedabove into a mold, which will typically be a square or rectangular mold,containing a stainless steel cylinder and allowing the base material tocongeal around the cylinder. Once the base material is congealed and thecrosslinking reaction has increased the melting temperature of thematerial to at least 60° C., the cylinder is removed and the moltengelatin inclusion material is poured into the resulting cylindricalopening and allowed to congeal. The mold is placed in an oven at about50° C. for a time sufficient to assure complete crosslinking of thegelatin by the crosslinking agent (typically at least 3 days).

[0058] Phantoms containing an agar/gelatin inclusion surrounded byoil-in-agar/gelatin base material are made substantially as describedabove, with the exception that the molten gel starting material thatgoes into both the inclusion and the base material is formed bycombining molten aqueous agar with molten aqueous gelatin. The dryweight percent agar will vary depending on the desired hardness of thematerial, however, for a typical phantom according to the presentinvention, the mixture will contain between about 1.0 and about 5percent agar and between about 3 and about 10 percent gelatin, based onthe dry weight of the materials. This includes embodiments wherein themixture contains between about 1.2 and about 4.3 percent agar andbetween about 3.9 and about 8.0 percent gelatin based on the dry weightof the materials.

[0059] A second aspect of the invention provides a tissue mimickingmaterial made from a gel-forming material suffused throughout theinterstices of an open-cell reticulated mesh material. These materialsmay take on a variety of shapes, but preferred shapes include spheresand cylinders. The mesh material is preferably a polymeric mesh havingbetween about 10 and about 30 cells per inch. Examples of suitable meshmaterials include polyurethane and polyether meshes. The gel-formingmaterial may be gelatin, including animal skin gelatin, or a mixture ofagar and gelatin. These materials may be crosslinked by adding acrosslinking agent to the gel-forming material during the congealingprocess. Suitable crosslinking agents have been described in more detailabove. The gel-forming material may also be pure agar. Because agarexhibits a nonlinear elasticity over strain ranges typically used inelastography studies (i.e. strains of up to at least 10%) using agar asthe gel-forming material provides a material that is more representativeof those cancers which possess nonlinear elasticities.

[0060] The tissue mimicking material of this aspect of the invention mayhave a double layered structure wherein an inner volume of gel-formingmaterial is suffused into an interior portion of the mesh material andan outer shell of gel-forming material is suffused into the meshmaterial around the inner volume, such that the outer shell is incontact with and partially or completely surrounds the inner volume.Preferably, the inner volume is comprised of pure agar and the outershell contains gelatin and a crosslinking agent. The inner volume andthe outer shell are held together with the mesh to prevent slipping atthe inner volume/outer shell interface. In one embodiment the mesh andthe inner volume and outer shell are spherical. In another embodiment,the inner volume which is contained within an interior portion of themesh material is substantially spherical in shape, while the outerportions of the mesh material and the outer shell gel-forming materialsuffused therein have spicule shaped arms extending outward from thecenter of the mesh material. This design mimicks tumors, such as breastcancer tumors, which are frequently spiculated.

[0061] The mesh-based tissue mimicking materials above may beincorporated as inclusions into a tissue mimicking base material to forma heterogeneous phantom. In this phantom the inclusions are at leastpartially surrounded by a base material comprising a gel-formingmaterial. The gel-forming material may comprise gelatin or a mixture ofagar and gelatin and may be the same gel-forming material found in theinclusion. In a preferred embodiment both the base and the inclusioncontain gelatin and the gelatin of the base and the gelatin of theinclusion are crosslinked. For such materials, there is no slipping atthe inclusion/base material interface.

[0062] Optionally, the gel-forming base and inclusion materials mayinclude additives designed to reproduce soft tissue-like elasticity,ultrasound, and magnetic resonance properties and to prolong the life ofthe phantom. These additives include solid scattering and attenuationparticles dispersed throughout the gel-forming material to increasebackscattering and attenuation levels. Other additives include organichydroxy compounds or a copper salt and a chelating agent to lower the T1value of the material. Optionally, the base or inclusion material mayinclude a preservative which protects the material against bacterialattack. These types of additives have already been discussed in greaterdetail above.

[0063] A heterogeneous phantom containing a simulated spiculated tumorcan be formed by imbedding the spiculated double layer materialdescribed above in a base material comprising a gelatin and acrosslinking agent. In a preferred embodiment, the inner volume of thedouble layer inclusion is composed of pure agar and simulates theelasticity, ultrasound, and magnetic resonance properties of anelastically nonlinear tumor, the outer shell contains gelatin andsimulates the elasticity, ultrasound, and magnetic resonance propertiesof tumor spiculations, and the base material contains gelatin andsimulates the elasticity, ultrasound, and magnetic resonance propertiesof normal tissues, such as fat and muscle.

[0064] Tissue mimicking materials composed of a single layer gel-formingmaterial suffused within the interstices of a mesh material can be madeaccording to the following general procedure. First a piece of meshmaterial is cut into the desired shape, typically a cylinder or asphere, and placed into a mold. Next, a molten gel-forming material isformed. This material may be the same type, and may be made by the sameprocess as the gel-forming material used to form the gelatin oragar/gelatin inclusions used in the oil-in-gelatin based phantomsdescribed above. The molten material is poured into the mold containingthe mesh material and allowed to infiltrate the pores. The material inthe mold is then allowed to congeal. The congealing process issubstantially the same process outlined above for the oil-in-gelatinbased materials. Once the congealing process is complete, the meshmaterial which is now embedded in the gel-forming material is removedfrom the mold and the excess gel forming material is removed from theoutside of the mesh either by trimming the material away or by immersingand swirling the embedded mesh in warm water until the excessgel-forming material melts away.

[0065] Tissue mimicking materials composed of a double layer gel-formingmaterial suffused within the interstices of a mesh material can be madeas follows. First a mesh material is cut into a desired shape. This maybe a generally smooth sphere or it may be a sphere having outerspicules, or arms, extending outwardly therefrom. The material is placedinto a mold. A first molten gel-forming material, which is preferably apure agar solution is then prepared and poured into the mold and allowedto infiltrate the pores in the mesh material. The mold is sealed and thegel-forming material is allowed to congeal. The gel embedded mesh isremoved from the mold and swirled in warm water until enough of thefirst gel-forming material has melted away to exposed the outer portionsof the mesh material, producing a mesh having a central volume ofgel-forming material. The mesh is then placed into a second mold and asecond molten gel-forming material, which is different from the firstmaterial, is poured into the mold. The mold is sealed and the secondgel-forming material is congealed around the first material to form asecond outer shell of material around the first shell. Again, the secondgel-forming material may be the same type, and may be made by the sameprocess as the gel-forming material used to form the gelatin oragar/gelatin inclusions used in the oil-in-gelatin based phantomsdescribed above.

[0066] Heterogeneous phantoms may be made from the above-describedmesh-based materials by embedding them as inclusions into a basematerial such that the they are at least partially surrounded by basematerial. The base materials may contain gelatin or a mixture of agarand gelatin. In addition, the base materials may be comprised ofoil-in-gelatin or oil-in-agar/gelatin dispersions of the type describedabove. The inclusions may be embedded in the base material by suspendingthe pre-formed inclusions in a large mold and pouring the base material,in a molten form, into the mold and congealing and crosslinking the basematerial, in a manner similar to that described above. Alternatively,phantoms having cylindrical inclusions can be formed by forming acongealed base with a cylindrical hole extending through it, inserting acylinder mesh into the hole, filling the cylindrical hole around themesh, and allowing any crosslinking reactions to be completed.

[0067] A third aspect of the invention provides a tissue mimickingmaterial made from millimeter sized agar spheres suspended within agelatin matrix. The agar spheres have a diameter of less than 5 mm, andpreferably less than 3 mm and are closely packed within the gelatinmatrix, accounting for at least 30 and preferably 70 volume percent ofthe material. The spheres are made from a mixture of agar powder andwater. Preferably, the dry weight concentration of agar in the mixtureis less than about 2 weight percent (70 grams per liter). For a moredetailed description of these materials, see R. B. Chin et al, Med.Phys., Vol. 17, pp. 380-390 (1990) and E. L. Madsen et al., Med. Phys.,Vol. 9, p. 703-710 (1982), both of which are incorporated by reference.

[0068] The materials of the present invention have a variety ofpractical applications, including the calibration, standardization andperformance assessment of elastography machines and the variousalgorithms used to create elastograms. The phantoms may also be used toassess the accuracy and resolution of an elastography instrument. Inaddition, anthropomorphic phantoms can be made to simulate complex bodystructures, such as a breast or prostate, in which multiple types oftissue (fat, muscle, tumor, etc.) are in contact with each other. Suchphantoms may be used to challenge elastography systems under developmentwith a more realistic elastographic system. Finally, because thephantoms can be designed to be tissue mimicking materials for use inboth ultrasound elastography and magnetic resonance elastographysystems, the same phantom can be used for direct performance comparisonsbetween the two modalities.

[0069] An exemplary elastography phantom that may be used for ultrasoundor magnetic resonance elastography is shown generally at 10 in FIGS. 4and 5. The phantom 10 includes a container 11 that encloses an interiorspace 12 in which tissue mimicking material may be held. The container11 may have any desired geometrical shape. For illustrative purposes,the walls of the container 11 enclosing the interior space 12 include abottom wall or base 15 and four side walls 16 that are joined to eachother to define a generally rectangular interior space 12. The containerwalls 15 and 16 may be made of any material that is liquid tight, ispreferably resistant to attack by the material held in the container,and does not interefere with ultrasound or MRI imaging, as appropriate.An example of a suitable material for the container walls 15 and 16 isacrylic plastic.

[0070] A block of tissue mimicking material 18 in accordance with theinvention is supported on the bottom wall 15 within the interior space12. The block of tissue mimicking material 18 is formed as describedabove, and may have the cubic form shown in FIGS. 4 and 5, althoughother geometries may also be utilized. The sides of the block ofmaterial 18 are preferably spaced from the side walls 16 to providespace for a surrounding bath of appropriate covering liquid 20, such asan oil (e.g., vegetable oil), which also covers the top surface 19 ofthe tissue mimicking material 18. The oil bath 20 is preferably utilizedto help prevent evaporation of liquid from the tissue mimicking material18. A cover 21 (e.g., also formed of acrylic) may be attached to thecontainer 11 (such as by the screws 23 shown in FIG. 4 threaded intotapped holes 24 in the container walls 16). The cover 21 further helpsto prevent loss of liquid from the material 18 (and a resilient gasket26 may be used between the cover 21 and the side walls 16 to furtherseal the interior of the container).

[0071] To use the phantom 10, the cover 21 is removed and a (typicallyflat) applicator is used to apply stress to the top surface 19 of thetissue mimicking material 18. In the dynamic type of MRI or ultrasoundimaging, the plate applies a sinusoidal shear or longitudinal stress,with a typical frequency of 60 Hz and an amplitude of 0.5 mm. In thequasi-static method for MRI or ultrasound, the plate compresses thetissue mimicking material 18 vertically (i.e., between the top surface19 and the bottom wall 15). Other shapes may be used for the tissuemimicking material, including anthropomorphic shapes, if desired.

[0072] The phantoms of the present invention thus can be readilymanufactured and are easy to use.

[0073] The production of tissue mimicking materials made from variousgel-forming materials and having various gel proportions are illustratedin the non-limiting examples presented below.

EXAMPLES Example 1

[0074] A heterogeneous phantom composed of a 50% oil-in-gelatin basematerial with a gelatin inclusion was made according to the followingsteps. First, 15.4 grams of dry weight 200 bloom calfskin gelatin(obtained from Vyse Gelatin Co.) was added to 100 ml of distilled water.The mixture was heated in a double boiler until it clarified at atemperature of about 90° C. Next, the mixture was cooled to 55° C., 1gram of thimerosal per liter of mixture was added, and 50% by volume ofsafflower oil (also at 55° C.) was added to the mixture along with 1 mlof liquid detergent. The detergent reduces the surface tension,facilitating the formation of microscopic droplets during agitation.Enough glass beads were added to produce a mixture composed of 4 gramsof glass beads per liter of mixture. The glass beads had a 22 μm meandiameter. The resulting mixture was mixed in a blender operated at lowspeed powered by a Variac power supply intermediary. Afteremulsification, the mixture was cooled to 36° C. and 7 ml of formalinsolution (i.e., a 37% aqueous formaldehyde solution) per liter of themolten gelatin mixture was added. The mixture was then poured into a 9cm×9 cm×9 cm square mold having a 2 cm diameter stainless steel cylinderextending through it. The mold was sealed, placed under positive gaugepressure, and rotated around a horizontal axis for 12 hours allowing themixture to congeal fully. The stainless steel cylinder was then removedand a molten calfskin gelatin mixture was poured into the resultingcylindrical hole and allowed to congeal. The molten gelatin had the samecomposition and was produced in the same way as that which had beenmixed with the safflower oil to produce the background material,including 1 gram per liter of thimersal. The molten gel also contained 4grams per liter of 22 μm diameter glass beads as the backgroundemulsion. The mold was then placed in an oven for 10 days at 55° C. tocomplete the crosslinking of the gelatin.

[0075] The background material mimics breast glandular tissue in termsof elasticity and ultrasound parameters. Also, the NMR T1 value was 495ms which is a reasonable value mimicking breast glandular tissue.

[0076]FIG. 1 shows an ultrasound elastogram (gray-scale mapping of localelastic strains) (left) and a magnetic resonance electrogram (right) forthe material of Example 1. The ultrasound elastogram was acquired with a7.5 MHz scan head with a 60% band width on a model SSD-2000 Alokascanner. The method for obtaining the ultrasound elastograms isdescribed in Ophir, J. et al, “Elastography: a quantitative method forimaging the elasticity of biological tissues,” Ultrasonic Imaging, Vol.13, 1991, pp. 11-134, which is incorporated herein by reference.Briefly, an apparatus has a 10 cm×10 cm flat aluminum plate with theultrasound transducer affixed so that the beam passes through a slot inthe plate. The plate is parallel to a base on which the phantom sits.The phantom and plate are submersed in safflower oil. The plate islowered to slightly compress the phantom and an ultrasound image isdigitized. The plate is lowered to slightly again, compressing thephantom additionally by 1%, and a second ultrasound image obtained.Software then computes the local elastic strains by comparing the twoimages.

[0077] Ultrasound, elastic, and magnetic resonance properties of thematerials are listed in Tables 1 and 2.

Example 2

[0078] A heterogeneous phantom composed of a 32% oil-in-gelatin basematerial with a graphite-in-gelatin inclusion was made according to thefollowing steps.

[0079] The 32% oil-in-gelatin background emulsion material was made inthe same manner as that in the phantom of Example 1, except that thevolume percent safflower oil was 32% instead of 50% and theconcentration of detergent was reduced by a factor of {fraction(32/50)}. This background emulsion also contained 4 grams per liter of22 μm diameter glass beads.

[0080] The graphite-in-gelatin inclusions was made using the same moltengelatin formulation as that used in forming the background material but,instead of making an emulsion, 50 grams per liter of No. 9039 powderedgraphite (Superior Graphite Co., Chicago, Ill.) was added. Four gramsper liter of 22 μm diameter glass beads were also added.

[0081] Both background and inclusion contain 7 ml of formalin per literof molten gelatin.

[0082]FIG. 2 shows three ultrasound elastograms (right) for the materialof Example 2, taken over a two-month period. The ultrasound elastogramswere acquired with a 7.5 MHz scan head with a 60% band width on a modelSSD-2000 Aloka scanner.

[0083] Ultrasound, elastic, and magnetic resonance properties of thematerials are listed in Tables 1 and 2.

Example 3

[0084] A heterogeneous phantom composed of a 50% oil-in-agar/gelatinbase material with an agar/gelatin inclusion was made according to thefollowing steps.

[0085] A molten aqueous agar solution was produced consisting of 10.2grams of dry agar and 500 cc of distilled water, and a molten gelatinsolution was made with 42 grams of dry 200 bloom calfskin gelatin and400 cc of distilled water. Both solutions were clarified at 90° C., thenlowered to 55° C. Then 280 cc of the gelatin solution and 420 cc of theagar solution were mixed together at 55° C., followed by addition of0.42 grams of CuCl₂.2H₂O (MW=170.5), 0.91 grams of the tetrasodiumhydrate salt of EDTA (MW=380.2), 5.6 grams NaCl, and 0.7 grams ofthimerosal.

[0086] To make the background emulsion, 600 cc of the 55° C. moltenagar/gelatin solution described above were mixed with 600 cc ofsafflower oil, also at 55° C. Ten cc of detergent (Ivory Liquid®,Proctor and Gamble Co.) were then added and the mixture stirredvigorously to complete emulsification. The 1200 cc of mixture was cooledto 35° C. and 1.4 cc of formalin was added to the mixture. The resultingmixture was cooled to 28° C., poured into a cubic mold and rotated abouta horizontal axis at 2 RPM for 12 hours during which time completecongealing occurred.

[0087] The cubic mold had a 2 cm diameter stainless steel cylinderextending through it, and that cylinder was withdrawn to allowintroduction of the molten inclusion material. The method for making theinclusion material is given above except that safflower oil anddetergent were not added. Instead, to a 1200 cc agar/gelatin CuCl₂.2H₂OEDTA/NaCl/thimersal mixture at 55° C., 24 grams of 22 μm diameter glassbeads were added. The mixture was cooled to 35° C. and 2.8 cc offormalin added. Finally, the resulting mixture is cooled to 30° C. andpoured into the cylindrical opening in the phantom and allowed tocongeal.

[0088]FIG. 3 shows two ultrasound elastograms for the material ofExample 3 taken eleven days apart. The ultrasound elastogram wasacquired with a 7.5 MHz scan head with a 60% band width on a modelSSD-2000 Aloka scanner.

[0089] Ultrasound, elastic, and magnetic resonance properties of thematerials are listed in Tables 1 and 2.

Example 4

[0090] Cylindrical samples of tumor mimicking materials composed ofgelatin suffused in a polymer mesh were made according to the followingsteps. These cylinders were in a shape providing for Instron measurementof Young's moduli. First, four polymer mesh cylinders having diametersof 2.5 cm and a heights of 1.0 cm were cut out of polymer mesh. Two ofthe cylinders were cut out of polyether mesh and two of the cylinderswere cut out of polyurethane mesh. One of the polyurethane cylinders andone of the polyether cylinders had 10 cells per inch. The other twocylinders each had 30 cells per inch. Each of the cylinders was placedinto a separate mold. A molten gelatin solution was made by combining23.1 grams of dry weight calfskin gelatin in 150 ml of distilled water.The mixture was heated until it clarified at a temperature of about 90°C. at which time 0.15 grams of thimerosal per liter of mixture wasadded. The mixture was cooled to 35° C. and 7° ml of formalin solutionper liter of the molten gelatin was added to the mixture. The molds wereclosed and baked at 50° C. for three days to allow the gelatin tocongeal and crosslink. After three days the materials were removed fromthe molds and the excess gelatin was trimmed from the outside of themesh.

[0091] Ultrasound, elastic, and magnetic resonance properties for thematerials are listed in Tables 1 and 2.

Example 5

[0092] A heterogenous phantom was made where the inclusions andbackground are oil-in-gelatin emulsions, and where contrast results fromdifferences in the oil concentrations in the materials. The gel matrixmaterial has the same composition throughout the phantom as in the aboveexamples.

[0093] A variable contrast “spherical lesion” phantom was made with 50%safflower oil-in-gelatin emulsion as the background material and threelower oil concentrations in the inclusions. Diagrams of two views of thephantom are shown in FIGS. 6 and 7. There were 3 sets of spheres madewith 30% safflower oil, another 3 sets with 15% safflower oil andanother 3 sets made with 0% safflower oil. Each set of spheres consistof a 3 mm, a 4 mm and a 6 mm-diameter sphere.

[0094] The gelatin matrix for all materials was made as follows. 750 ccof distilled water was combined with 115.4 grams of 200 bloom calfskingelatin and brought to 90° C. until the mixture clarified. The moltengel was cooled to 55° C. and 0.75 grams of thimerosal was added to themixture. The background materials was formed from 750 cc of theresulting molten gel by adding 750 cc of safflower oil at 55° C. and16.7 cc of Ivory Liquid® detergent. Emulsification was produced byagitation with a spoon in a way that no air bubbles were introduced.Next, 4 grams per liter of 22 μm diameter glass beads were dispersed inthe emulsion and it was cooled to 35° C. A 5.25 cc quantity of formalinwas added and the molten gel cooled to 30° C. at which time the materialwas ready to be poured into a 10×10×10 cm³ mold for congealing.

[0095] Before the 50% oil-in-gelatin background material was introduced,all spherical inclusions were made and positioned in the 10×10×10 cm³mold. The 30% oil-in-gelatin emulsion was made in the same fashion asthe background except that the oil composed 30% by volume and theconcentration of detergent was ⅗ of that in the background material. Theconcentration of formalin was kept proportional to the concentration ofgelatin and the concentration of 22 μm diameter glass beads was kept at4 grams per liter of the final emulsion. The 15% and 0% emulsions wereproduced accordingly.

[0096] For each oil concentration in the inclusion, spheres were made byimmersing a two-part acrylic mold in the molten material and closing themold. Each side of the mold has hemispherical depressions of theappropriate diameters. The depressions exist in flat surfaces and thedepressions are positioned so that, when the two parts are broughttogether, the hemispheres align so that spherical volumes of molten gelare formed. Cylindrical pegs and holes assure proper alignment of thetwo parts of the mold. After the two parts of the mold have been broughttogether in the molten gel, the mold is removed and a C-clamp applied tokeep the two parts together. Then the mold and C-clamp are attached to arotation device and rotation at 2 rpm about a horizontal axis followeduntil the spheres have congealed. The first step in production of thephantom is to suspend the spheres on 0.3 mm-diameter stainless steelwires in the desired arrangement in the 10×10×10 cm³ mold. The moltenbackground material (50% oil-in-gelatin) is introduced, the cavitysealed under positive gauge pressure, and the entire apparatus rotatedat 2 rmp about a horizontal axis until congealing has completed. Twelvehours rotating is routine.

[0097] After congealing, the stainless steel wires are withdrawn leavingthe solid spheres in the desired spatial arrangement and surrounded bythe background material.

[0098] Ultrasound and elastic properties of the phantom componentmaterials at 22° C. are given in Tables 1 and 2.

[0099] Note that neither the phantom nor test samples were baked at 50°C. following completion of the phantom. This explains the higher valuesof Young's moduli than for earlier similar materials, which had beenbaked.

[0100] It is noted that there is a difference in the way gel hardness iscontrolled in a heterogeneous phantom for the gelatin-only and thegelatin/agar tissue mimicking materials. Hardness differences in thegelatin materials relates to the concentration of oil in the emulsion.An oil emulsion is not necessary to make hardness differences in thegelatin/agar materials. With no oil in the gelatin/agar material, thegelatin concentration is kept constant everywhere, with the dry-weightagar concentration being the variable on which hardness depends. Oilemulsions can also be used with the gelatin/agar materials, if desired.

[0101] After the materials in Examples 1-5 were formed according to themethods above, the Young's moduli, the speed of sound in the materials,the attenuation coefficients, and, in some instances, the NMR relaxationtimes and elastic contrasts were measured at selected frequencies foreach of the inclusion materials and each of the base materials. Theresults of these measurement are presented in Tables 1 and 2. In somecases, Table 2 includes Young's modulus values taken over the course ofseveral months. Methods for taking ultrasound and NMR measurements arewell known in the art and have been described previously in Madsen etal., “Interlaboratory comparison of ultrasonic backscatter, attenuationand speed,” J. Ultrasound in Med. 18, 615-631 (1999); Blechinger et al.,“Tissue mimicking gelatin-agar gels for use in magnetic resonanceimaging phantoms,” Med. Phys. 15, 629-636 (1988); and D'Souze et al.,“Tissue mimicking materials for a multi-imaging modality prostatephantom,” Med. Phys. 28, 688-700 (2001), which are incorporated hereinby reference.

[0102] Briefly, the ultrasound parameters of the tissue mimickingmaterials were measured as follows for cyclindrical inclusions of thetype described in the examples above. Tissue mimicking cylindricalinclusion samples were placed in a constant temperature water bath(maintained at 22° C.) between a transmitting transducer and receivingtransducer. The parallel faces of the samples were maintainedperpendicular to the ultrasound beam direction.

[0103] The speed of sound was measured by measuring the difference inthe pulse arrival time for the cases in which the sample is present andabsent between the transmitting and receiving transducer. The speed ofsound in the tissue mimicking material sample was then calculatedrelative to the speed of sound in distilled water. The ultrasonicattenuation coefficient at four discrete frequencies was measured withthe same experimental setup. This was done by noting the pulseamplitudes when the sample is present and absent from the path of theultrasound beam. Corrections for the nonzero thickness of thin plasticlayers over the parallel sample faces are significant for frequenciesabove about 2 MHz and are included in the data reduction.

[0104] For magnetic resonance imaging, hydrogen T1 and T2 relaxationtimes are parameters of interest. Measurements were performed on smallsamples in 5 mm diameter NMR tubes of the tissue mimicking materials ofinterest using a 40 MHz Minispec spectrometer (Bruker, Canada) alongwith supporting equipment consisting of an IBM computer, a storageoscilloscope, and a constant temperature water bath maintained at atemperature slightly below 22° C. The 40 MHz spectrometer probe ismaintained at 40° C. In order to make measurements at 22° C., the sampleplaced in the water bath initially is then inserted in the spectrometerprobe. Data is acquired within 1.5 minutes to avoid significanttemperature rise of the sample. It has been shown that the temperaturerise within the first minute is less than 2° C. The spectrometer wasinterfaced with the computer which uses software from IBM Instruments(Danbury, Conn.) for pulse programming and data acquisition. The optimumpulse durations were found by maximizing the initial signal for a 90°pulse and minimizing the absolute value of the entire free inductiondecay (FID) for the 180° pulse.

[0105] An inversion recovery (IR) sequence was used to obtain the datafor the longitudinal relaxation time. A relaxation time (TR) of at leastfive times the expected T1 was used. The T1 experiment was repeated tentimes. Data reduction was done by curve fitting to an expression of theform:

M(t)=M ₀(1−2exp(−t/T1))  (1)

[0106] where M(t) is the instantaneous magnetization, M₀ is the initiallongitudinal magnetization (thermal equilibrium), and t is the time atwhich each data point is acquired in the experiment. The uncertainty inthe measurement of M(t) is calculated and this uncertainty is propagatedto calculate the estimated uncertainty in T1.

[0107] The CPMG spin-echo pulse sequence was used to measure thetransverse relaxation time. The relaxation delay (repetition time) wasset to 5 times T1 and data was acquired for τ (τ=one-half the echo time,TE) values of 25 μs, 125 μs, 250 μs, and 500 μs. 255 echo peaks wererecorded in each CPMG sequence. The data obtained was fitted to a singleexponential of the form:

M(t)=M ₀ exp(−t/T2)  (2)

[0108] where M(t) is the instantaneous magnetization at time t, M₀ isthe initial magnetization and T2 is the transverse relaxation time.

[0109] The Young's modulus for each of the materials in Table 2 wasobtained as follows. A hydraulic servo Instron™ 8500 from the Universityof Texas-Houston Dental School was employed. When measurements were notbeing made, the samples were stored in safflower oil to preventdessication. First, a clean smooth flat plate was placed in the Instronmachine and raised until it contacted a compressor. The compressor isconnected directly to a load cell in the machine. When the load cellregistered a load of 0.8 grams, the elevation of a reference point isrecorded and used to zero the height of the samples. A cylindricalsample of the material to be characterized was removed from thesafflower oil and placed on the flat plate in the Instron. A thin layerof oil clinging to each sample prevents desiccation of the materialduring the measurement and suppresses undesirable shear forces duringthe measurements. The system is then activated to cause the sample tocome into contact with the compressor. Once a load of 0.8 grams wasregistered, the position was recorded and used to calculate the heightof the sample. The Instron was programmed to apply a load yielding a 10%strain to the sample at a rate of 1% per second. After each test wasrecorded by the Instron, the system was returned to zero strain and thesample was given three minutes to recover. The procedure was repeateduntil the final load was less than one gram different than for theoriginal measurement. If there was a load difference of more than onegram, the test was repeated four times and the data averaged forcalculating the modulus over the strain range of 0-10%. The gel samplewas then returned to the safflower oil for storage at room temperature.The test results were stored as stress-strain curves. The slope of thestress-strain curves yielded the value of E for each material. TABLE 1Values of Elastic, Ultrasound and Magnetic Resonance Properties ofTissue Mimicking Materials. Attenu- Ultra- ation sound Coef- Propa-ficient gation Frequency Speed (db/cm/ T1 T2 Material (m/s) MHz) (ms)(ms) Example 1: Gelatin Inclusion 1536 0.179 1219 653 Example 1: 50%Oil-in-Gelatin Base 1496 0.320 452 285 Example 2: Graphite-in-Gelatin1533 0.540 Inclusion* Example 2: 32% Oil-in-Gelatin Base* 1506 0.743Example 3: Agar/Gelatin Inclusion 1516 0.188 787 127 Example 3: 50%Oil-in-Agar/Gelatin 1488 0.423 693 152 Base Example 4: 10 Cells/inchPolyether (PE) in Gelatin Inclusion Example 4: 30 Cells/inch Polyetherin Gelatin Inclusion Example 4: 10 Cells/inch Poly- urethane in GelatinInclusion Example 4: 30 Cells/inch Poly- urethane in Gelatin InclusionExample 5: 50% Oil-in-Gelatin Base 1497 0.38 Example 5: 30%Oil-in-Gelatin 1514 0.32 Inclusion Example 5: 15% Oil-in-Gelatin 15260.28 Inclusion Example 5: 0% Oil-in-Gelatin 1540 0.15 Inclusion

[0110] TABLE 2 Values of Young's Modulus (E) over time and ElasticContrast for Tissue Mimicking Materials. Young's modulus (kPa) ElasticMaterial Day 1 Day 105 Day 120 Day 158 Contrast Example 1: GelatinInclusion  27 Example 1: 50% Oil-in-Gelatin Base  10 Example 2:Graphite-in-Gelatin Inclusion* 29, 29, 27 38, 34, 36 41, 38, 37 Example2: 32% Oil-in-Gelatin Base* 16, 19, 17 20, 20, 23 23, 25, 23 Example 3:Agar/Gelatin Inclusion  13  13 Example 3: 50% Oil-in-Agar/Gelatin Base 3  3 Example 4: 10 Cells/inch Polyether in Gelatin Inclusion  89  82 89 Example 4: 30 Cells/inch Polyester in Gelatin Inclusion 131 126 129Example 4: 10 Cells/inch Polyurethane in Gelatin Inclusion  60  68  90Example 4: 30 Cells/inch Polyurethane in Gelatin Inclusion  61  75  80Example 5: 50% Oil-in-Gelatin Base  40 1.00 Example 5: 30%Oil-in-Gelatin Inclusion  66 1.65 Example 5: 15% Oil-in-GelatinInclusion  86 2.15 Example 5: 0% Oil-in-Gelatin Inclusion 103 2.58

Example 6

[0111] This example demonstrates the effect of baking time on theYoung's moduli of the gel-based materials of the invention. Four samplesof plain gelatin, made according to the procedure in Example 1, and foursamples of 50% oil-in-gelatin emulsion, also made according to theprocedure in Example 1, were baked at 50° C. for baking times of between0 and 15 days.

[0112] The Young's modulus for each material was measured according tothe procedures outlined above at various intervals after baking wascompleted to illustrate the stability of the Young's moduli of thematerials. The results of the measurements are shown in Tables 3 and 4.TABLE 3 Young's Moduli for the Six Plain Gelatin Samples With Different50° C. Baking Periods. The Samples Were Made on 28 Dec. 2002. NumberYoung's Modulus After . . . Sample of Days 19 31 55 88 111 142 # BakedDays Days Days Days Days Days 1 0 104 — 123 115 106 107 2 5 31 — 33 — 3431 3 10 22 — 29 27 27 25 4 15 17 — 28 24 22 24

[0113] TABLE 4 Young's Moduli for the Six 50% Oil-in-Gelatin EmulsoinSamples With Different 50° C. Baking Periods. The Samples Were Made on28 Dec. 2002. Young's Modulus After . . . Sample Number 19 31 55 88 111142 # of Days Days Days Days Days Days Days 1 0 38 — 43 42 43 37 2 5 13— 14 — 14 13 3 10 11 — 13 13 13 12 4 15 8 — 10 12 10 9

[0114] The data in Tables 3 and 4 show a pronounced decrease in theYoung's moduli in the materials with increased baking time.

[0115] It is understood that the invention is not confined to theparticular embodiments described herein, but embraces all such formsthereof as come within the scope of the following claims.

What is claimed is:
 1. A tissue mimicking material for testingelastography imagers, comprising: (a) a base material comprising an oildispersed throughout a gel matrix formed from a gel-forming material;and (b) at least one inclusion of a defined shape at least partiallysurrounded by the base material, the inclusion comprising the samegel-forming material as the base material, wherein the elastic contrastbetween the base material and the at least one inclusion is such thatthe elastic contrast between normal soft tissue and abnormal soft tissueis mimicked, making the tissue mimicking material suitable for use intesting elastography imagers.
 2. The tissue mimicking material of claim1 wherein the elastic contrast between the base material and the atleast one inclusion is between about 1 and about
 4. 3. The tissuemimicking material of claim 1 wherein the elastic contrast between thebase material and the at least one inclusion is between about 1 andabout
 3. 4. The tissue mimicking material of claim 1 wherein the basematerial is elastically linear for strains of up to about 10 percent. 5.The tissue mimicking material of claim 1 wherein the speed of sound inthe base material and the at least one inclusion is between about 1300m/s and about 1650 m/s.
 6. The tissue mimicking material of claim 1wherein the T1 values of the base material and the at least oneinclusion are between about 200 ms and about 1200 ms, and the T2 valuesof the base material and the at least one inclusion are between about 40ms and about 700 ms.
 7. The tissue mimicking material of claim 1 whereinthe elastic contrast between the base material and the at least oneinclusion varies by less than about 20% over a period of at least sixmonths.
 8. The tissue mimicking material of claim 1 wherein thegel-forming material comprises gelatin or a mixture of agar and gelatin.9. The tissue mimicking material of claim 1 wherein the base materialand the at least one inclusion both comprise an oil-in-gelatindispersion and further wherein the concentration of oil in the basematerial differs from the concentration of oil in the at least oneinclusion.
 10. The tissue mimicking material of claim 1 wherein thegel-forming material in at least one of the base material or the atleast one inclusion further comprises at least one additional additiveselected from the group consisting of a crosslinking agent, an organichydroxy compound, microscopic solid particles, a copper salt, achelating agent, and an agent for inhibiting attack by microorganisms.11. The tissue mimicking material of claim 1 wherein the oil is selectedfrom the group consisting of safflower oil, olive oil, castor oil, andkerosene.
 12. An abnormal tissue mimicking material for testingelastography imagers comprising an open-cell reticulated mesh materialand a gel-forming material suffused into the mesh material, wherein theYoung's modulus of the abnormal tissue mimicking material mimics theYoung's modulus of abnormal soft tissue.
 13. The abnormal tissuemimicking material of claim 12 wherein the Young's modulus of theabnormal tissue mimicking material is between about 10 and about 300kPa.
 14. The abnormal tissue mimicking material of claim 12 wherein theopen-cell reticulated mesh material is a polyether mesh or apolyurethane mesh.
 15. The abnormal tissue mimicking material of claim12 wherein the open-cell reticulated mesh material comprises betweenabout 10 and about 30 cells per inch.
 16. The abnormal tissue mimickingmaterial of claim 12 wherein the gel-forming material comprises amaterial selected from the group consisting of gelatin, agar, a mixtureof gelatin and agar, an emulsion of oil-in-gelatin, and an emulsion ofoil in a mixture of agar and gelatin.
 17. The abnormal tissue mimickingmaterial of claim 12 wherein the gel-forming material comprises agar.18. The abnormal tissue mimicking material of claim 17 wherein thematerial is elastically nonlinear for strains of up to about 10 percent.19. The abnormal tissue mimicking material of claim 12 wherein thegel-forming material further comprises at least one additional additiveselected from the group consisting of a crosslinking agent, an organichydroxy compound, microscopic solid particles, a copper salt, achelating agent, and an agent for inhibiting attack by microorganisms.20. The abnormal tissue mimicking material of claim 12 wherein thegel-forming material comprises an inner volume comprising agar suffusedinto the mesh material and an outer shell comprising gelatin suffusedinto the mesh material, wherein the outer shell surrounds the innervolume.
 21. The abnormal tissue mimicking material of claim 20 whereinthe outer shell comprises a mixture of agar and gelatin.
 22. Theabnormal tissue mimicking material of claim 22 wherein the inner volumeis substantially spherically shaped and the outer shell has a pluralityof spicules extending outward away from the inner volume.
 23. A tissuemimicking material for testing elastography imagers, comprising: (a) abase material comprising a gel-forming material; and (b) at least oneinclusion comprising the abnormal tissue mimicking material claim 12 atleast partially surrounded by the base material, wherein the elasticcontrast between the base material and the at least one inclusion issuch that the elastic contrast between normal soft tissue and abnormalsoft tissue is mimicked, making the tissue mimicking material suitablefor use in testing elastography imagers.
 24. The tissue mimickingmaterial of claim 23 wherein the elastic contrast between the basematerial and the at least one inclusion is between about 1 and about 4.25. The tissue mimicking material of claim 23 wherein the elasticcontrast between the base material and the at least one inclusion isbetween about 1 and about
 3. 26. The tissue mimicking material of claim23 wherein the speed of sound in the base material and the at least oneinclusion is between about 1300 and 1650 m/s.
 27. The tissue mimickingmaterial of claim 23 wherein the T1 values of the base material and theat least one inclusion are between about 200 ms and about 1200 ms andthe T2 values of the base material and the at least one inclusion arebetween about 40 ms and about 200 ms.
 28. The tissue mimicking materialof claim 23 wherein the elastic contrast between the base material andthe at least one inclusion varies by less than about 20% over a periodof at least six months.
 29. The tissue mimicking material of claim 23wherein the gel-forming material in the base material is selected fromthe group consisting of gelatin, agar, or a mixture of gelatin and agar.30. An elastography phantom comprising: (a) an elastography phantomcontainer enclosing an interior space; and (b) the tissue mimickingmaterial of claim 1 contained within the interior space of thecontainer.
 31. An elastography phantom comprising: (a) an elastographyphantom container enclosing an interior space; and (b) the tissuemimicking material of claim 23 contained within the interior space ofthe container.
 32. A method for testing an elastography imagercomprising, mapping local elastic strains of a tissue mimicking materialto obtain a elastogram of the tissue mimicking material, the tissuemimicking material comprising: (i) a base material comprising an oildispersed throughout a gel matrix formed from a gel-forming material;and (ii) at least one inclusion of a defined shape at least partiallysurrounded by the base material, the inclusion comprising the samegel-forming material as the base material, wherein the elastic contrastbetween the base material and the at least one inclusion is such thatthe elastic contrast between normal soft tissue and abnormal soft tissueis mimicked.
 33. The method of claim 32 wherein the elastogram is anultrasound elastogram or a magnetic resonance elastogram.
 34. A methodfor testing an elastography imager comprising, mapping local elasticstrains of a tissue mimicking material to obtain a elastogram of thetissue mimicking material, the tissue mimicking material comprising: (i)a base material comprising a gel-forming material; and (ii) at least oneinclusion of a defined shape at least partially surrounded by the basematerial, the at least one inclusion comprising an open-cell reticulatedmesh material and a gel-forming material suffused into the meshmaterial, wherein the elastic contrast between the base material and theat least one inclusion is such that the elastic contrast between normalsoft tissue and abnormal soft tissue is mimicked.
 35. The method ofclaim 34 wherein the elastogram is an ultrasound elastogram or amagnetic resonance elastogram.